For doctors

CoAprovel is a combination of two active substances, irbesartan and hydrochlorothiazide. Irbesartan belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin-II is a substance produced in the body that binds to receptors in blood vessels causing them to tighten. This results in an increase in blood pressure. Irbesartan prevents the binding of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. Hydrochlorothiazide is one of a group of medicines (called thiazide diuretics) that causes increased urine output and so causes a lowering of blood pressure. The two active ingredients in CoAprovel work together to lower blood pressure further than if either was given alone.

CoAprovel is used to treat high blood pressure, when treatment with irbesartan or hydrochlorothiazide alone did not provide adequate control of your blood pressure.

Do not take CoAprovel if you are allergic (hypersensitive) to irbesartan or any of the other ingredients of CoAprovel if you are allergic (hypersensitive) to hydrochlorothiazide or any other sulfonamide-derived medicines if you are more than 3 months pregnant. (It is also better to avoid CoAprovel in early pregnancy – see pregnancy section) if you have severe liver or kidney problemsif you have difficulty in producing urineif your doctor determines that you have persistently high calcium or low potassium levels in your blood

CoAprovel should not be given to children and adolescents (under 18 years).

Take special care with CoAprovel Tell your doctor if any of the following apply to you: if you get excessive vomiting or diarrhoeaif you suffer from kidney problems or have a kidney transplantif you suffer from heart problemsif you suffer from liver problemsif you suffer from diabetesif you suffer from lupus erythematosus (also known as lupus or SLE) if you suffer from primary aldosteronism (a condition related to high production of the hormone aldosterone, which causes sodium retention and, in turn, an increase in blood pressure).

You must tell your doctor if you think you are ( or might become) pregnant. CoAprovel is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).

You should also tell your doctor: if you are on a low-salt dietif you have signs such as abnormal thirst, dry mouth, general weakness, drowsiness, muscle pain or cramps, nausea, vomiting, or an abnormally fast heart beat which may indicate an excessive effect of hydrochlorothiazide (contained in CoAprovel) if you experience an increased sensitivity of the skin to the sun with symptoms of sunburn (such as redness, itching, swelling, blistering) occurring more quickly than normal if you are going tohave an operation (surgery) or be given anaesthetics

The hydrochlorothiazide contained in this medicine could produce a positive result in an anti-doping test.

Using other medicines Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Diuretic agents such as the hydrochlorothiazide contained in CoAprovel may have an effect on other medicines. Preparations containing lithium should not be taken with CoAprovel without close supervision by your doctor.

You may need to have blood checks if you take: potassium supplements salt substitutes containing potassium potassium sparing medicines or other diuretics (water tablets) some laxatives medicines for the treatment of gout therapeutic vitamin D supplements medicines to control heart rhythm medicines for diabetes (oral agents or insulins)

It is also important to tell your doctor if you are taking other medicines to reduce your blood pressure, steroids, medicines to treat cancer, pain killers, arthritis medicines, or colestyramine and colestipol resins for lowering blood cholesterol.

Taking CoAprovel with food and drink CoAprovel can be taken with or without food.

Due to the hydrochlorothiazide contained in CoAprovel, if you drink alcohol while on treatment with this medicine, you may have an increased feeling of dizziness on standing up, specially when getting up from a sitting position.

Pregnancy and breast-feeding Pregnancy You must tell your doctor if you think you are ( or might become) pregnant. Your doctor will normally advise you to stop taking CoAprovel before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of CoAprovel. CoAprovel is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.

Breast-feeding Tell your doctor if you are breast-feeding or about to start breast-feeding. CoAprovel is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely.

Driving and using machines No studies on the effects on the ability to drive and use machines have been performed. CoAprovel is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or weariness may occur during treatment of high blood pressure. If you experience these, talk to your doctor before attempting to drive or use machines.

Important information about some of the ingredients of CoAprovel CoAprovel contains lactose. If you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), contact your doctor before taking this medicine.

Always take CoAprovel exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Dosage The usual dose of CoAprovel is one or two tablets a day. CoAprovel will usually be prescribed by your doctor when your previous treatment did not reduce your blood pressure enough. Your doctor will instruct you how to switch from the previous treatment to CoAprovel.

Method of administration CoAprovel is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). You can take CoAprovel with or without food. Try to take your daily dose at about the same time each day. It is important that you continue to take CoAprovel until your doctor tells you otherwise.

Like all medicines, CoAprovel can cause side effects, although not everybody gets them. Some of these effects may be serious and may require medical attention.

Rare cases of allergic skin reactions (rash, urticaria), as well as localised swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any of the above symptoms or get short of breath, stop taking CoAproveland contact your doctor immediately.

Side effects reported in clinical studies for patients treated with CoAprovel were:

Common side effects(affect 1 to 10 users in 100)nausea/vomiting abnormal urination fatigue dizziness (including when getting up from a lying or sitting position) blood tests may show raised levels of an enzyme that measures the muscle and heart function (creatine kinase) or raised levels of substances that measure kidney function (blood urea nitrogen, creatinine). If any of these side effects causes you problems, talk to your doctor.

Uncommon side effects(affect 1 to 10 users in 1,000)diarrhoea low blood pressure fainting heart rate increased flushing swelling sexual dysfunction (problems with sexual performance) blood tests may show lowered levels of potassium and sodium in your blood. If any of these side effects causes you problems, talk to your doctor.

Side effects reported since the launch of CoAprovel The frequency of these effects is not known. These undesirable effects are: headache, ringing in the ears, cough, taste disturbance, indigestion, pain in joints and muscles, liver function abnormal and impaired kidney function, increased level of potassium in your blood and allergic reactions such as rash, hives, swelling of the face, lips, mouth, tongue or throat.

As for any combination of two active substances, side effects associated with each individual component cannot be excluded. Side effects associated with irbesartan alone In addition to the side effects listed above, chest pain has also been reported. Side effects associated with hydrochlorothiazide alone Loss of appetite; stomach irritation; stomach cramps; constipation; jaundice (yellowing of the skin and/or whites of the eyes); inflammation of the pancreas characterised by severe upper stomach pain, often with nausea and vomiting; sleep disorders; depression; blurred vision; lack of white blood cells, which can result in frequent infections, fever; decrease in the number of platelets (a blood cell essential for the clotting of the blood), decreased number of red blood cells (anaemia) characterised by tiredness, headaches, being short of breath when exercising, dizziness and looking pale; kidney disease; lung problems including pneumonia or build-up of fluid in the lungs; increased sensitivity of the skin to the sun; inflammation of blood vessels; a skin disease characterized by the peeling of the skin all over the body; cutaneous lupus erythematosus, which is identified by a rash that may appear on the face, neck, and scalp; allergic reactions; weakness and muscle spasm; altered heart rate; reduced blood pressure after a change in body position; swelling of the salivary glands; high sugar levels in the blood; sugar in the urine; increases in some kinds of blood fat; high uric acid levels in the blood, which may cause gout.

It is known that side effects associated with hydrochlorothiazide may increase with higher doses of hydrochlorothiazide.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

For doctors

CoAprovel is a medicine that contains two active substances, irbesartan and hydrochlorothiazide. It is available as oval tablets (peach: 150 mg or 300 mg irbesartan and 12.5 mg hydrochlorothiazide; pink: 300 mg irbesartan and 25 mg hydrochlorothiazide).

CoAprovel is used in adults who have essential hypertension (high blood pressure) that is not adequately controlled by irbesartan or hydrochlorothiazide alone. ‘Essential’ means that the hypertension has no obvious cause. The medicine can only be obtained with a prescription.

CoAprovel is taken by mouth, with or without food. The dose of CoAprovel to be used depends on the dose of irbesartan or hydrochlorothiazide that the patient was taking before. Doses higher than 300 mg irbesartan and 25 mg hydrochlorothiazide once a day are not recommended. CoAprovel may be added to other treatments for hypertension.

CoAprovel contains two active substances, irbesartan and hydrochlorothiazide. Irbesartan is an ‘angiotensin II receptor antagonist’, which means that it blocks the action of a hormone in the body called angiotensin II. Angiotensin II is a powerful vasoconstrictor (a substance that narrows blood vessels). By blocking the receptors to which angiotensin II normally attaches, irbesartan stops the hormone having an effect, allowing the blood vessels to widen. Hydrochlorothiazide is a diuretic, which is another type of treatment for hypertension. It works by increasing urine output, reducing the amount of fluid in the blood and lowering the blood pressure. The combination of the two active substances has an additive effect, reducing the blood pressure more than either medicine alone. By lowering the blood pressure, the risks associated with high blood pressure, such as having a stroke, are reduced.

Irbesartan on its own has been approved in the European Union (EU) since 1997 under the names Karvea and Aprovel. It can be used with hydrochlorothiazide to treat hypertension. The studies of

Karvea/Aprovel used with hydrochlorothiazide as separate tablets were used to support the use of CoAprovel. Further studies were also carried out with doses of 300 mg irbesartan in combination with 25 mg hydrochlorothiazide. The main measure of effectiveness was the reduction in diastolic blood pressure (the blood pressure measured between two heartbeats).

CoAprovel was more effective than placebo (a dummy treatment) and than hydrochlorothiazide alone in reducing diastolic blood pressure. Increasing the dose to 300 mg irbesartan and 25 mg hydrochlorothiazide may give a further decrease in blood pressure.

The most common side effects with CoAprovel (seen in between 1 and 10 patients in 100) are dizziness, nausea (feeling sick) or vomiting, abnormal urination, fatigue (tiredness), and increases in blood urea nitrogen (BUN, a breakdown product of protein), creatinine (a breakdown product of muscle) and creatine kinase (an enzyme found in muscle). For the full list of all side effects reported with CoAprovel, see the Package Leaflet. CoAprovel should not be used in people who may be hypersensitive (allergic) to irbesartan, hydrochlorothiazide, sulfonamides, or any of the other ingredients. It must not be used in women who are more than three months pregnant. Its use during the first three months of pregnancy is not recommended. CoAprovel must also not be used in patients who have severe liver, kidney or bile problems, blood potassium levels that are too low or blood calcium levels that are too high. Care must be taken when using CoAprovel with other medicines that have an effect on blood potassium levels. The full list of these medicines is given in the Package Leaflet.

The Committee for Medicinal Products for Human Use (CHMP) decided that CoAprovel’s benefits are greater than its risks for the treatment of essential hypertension in adult patients whose blood pressure is not adequately controlled on irbesartan or hydrochlorothiazide alone. The Committee recommended that CoAprovel be given marketing authorisation.

The European Commission granted a marketing authorisation valid throughout the EU for CoAprovel to Sanofi Pharma Bristol-Myers Squibb SNC on 15 October 1998. The marketing authorisation was renewed on 15 October 2003 and on 15 October 2008.